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Neuromuscular function is one of the important factors affecting athletic performance. Previous studies have shown that fish oil supplementation can improve performance. This study investigated the effect of fish oil on neuromuscular performance after exhausting exercise. Eighteen healthy men (mean ± standard deviation; age 26.9±2.6 years; weight 78.33±10.42 kg; height 175.8±4.9 cm; body fat percentage 18.40±5.46%) voluntarily participated and were randomly assigned to fish and corn oil groups in a double blind manner. Participants received 6 g/day of oil for 4 weeks, while maintaining baseline diet and training status during the study. Changes in maximal voluntary contraction (MVC) of the tibialis anterior muscle, neuromuscular propagation of tibialis anterior muscle (M-wave), corticospinal excitability (MEP: motor evoked potential), and the rate of perceived exertion (RPE) were evaluated before and after supplementation in response to a modified Bruce exhausting protocol. Group differences in changes in each variable following supplementation were assessed by two-way analysis of variances (ANOVA). Compared to corn oil, fish oil demonstrated less perceived exertion at the end of exhaustive exercise (F=9.72, P=0.001) after supplementation, and normalised MEP to M-wave showed a trend (F=3.83, P=0.071). However, M-wave peak to peak amplitudes changes were not significant between the groups (P>0.05). In addition, significant differences were observed between baseline MVC values of the group following supplementation. Thus, it seems that fish oil can improve corticospinal excitability, thereby improving neuromuscular function in exhausting activities. Therefore, fish oil supplementation may be recommended to increase performance in activities otherwise limited. However, the mechanism underlying this effect remains to be elucidated.

The adoptive transfer of donor-derived virus-specific T cells (VSTs) is an effective treatment for infections following allogeneic hematopoietic cell transplantation. Acute exercise mobilizes effector lymphocytes and VSTs to the circulation and augments the ex vivo manufacture of VSTs. This study determined if β(2) adrenergic receptor (AR) signaling precipitated the VST response to acute exercise. Healthy participants (n = 12) completed 30 min of steady-state cycling exercise after ingesting a placebo, a β(1 + 2) AR antagonist (nadolol) or a β(1) AR antagonist (bisoprolol). Circulating VSTs to cytomegalovirus (CMV), Epstein–Barr virus (EBV), and adenovirus (AdV) antigens were enumerated before and after exercise, and peripheral blood mononuclear cells were cultured with viral peptides for 8 days to expand multi-VSTs. Compared with placebo, nadolol blunted the exercise-induced mobilization of CMV-VSTs (Δ VSTs/100,000 CD3(+) T cells = 93 ± 104 vs. 22 ± 91 for placebo and nadolol, respectively; p = 0.036), while bisoprolol did not, despite both drugs evoking similar reductions in exercising heart rate and blood pressure. Circulating AdV and EBV VSTs (VSTs/mL blood) only increased after exercise with placebo. Although not significant, nadolol partially mitigated exercise-induced increases in multi-VST expansion, particularly in participants that demonstrated an exercise-induced increase in VST expansion. We conclude that exercise-induced enhancements in VST mobilization and expansion are at least partially β(2) AR mediated, thus highlighting a role for the β(2) AR in targeted therapy for the augmentation of VST immune cell therapeutics in the allogeneic adoptive transfer setting. Moreover, long-term regular exercise may provide additional viral protection in the host through frequent β(2) AR-dependent mobilization and redistribution of VSTs cumulated with each bout of exercise.

Purpose The nodlike receptor family pyrin domain containing 3 (NLRP3) inflammasome is a critical player in vascular pathology as it regulates caspase-1-mediated interleukin (IL)-1β processing. Physical activity ameliorates obesity-induced inflammation and vascular dysfunction, but the mechanisms responsible for these positive changes are incompletely understood. Here, the protective effect of physical activity on the inflammasome-associated vascular dysfunction in obesity and its putative mechanisms were investigated. Methods Mice were fed a control low-fat diet (LFD) or a high-fat diet (HFD; 45% of calories from fat) and provided with running wheel access (LF-RUN or HF-RUN) or denied wheel access for our sedentary condition (LF-SED or HF-SED). The NLRP3 inflammasome-associated pathway, including NLRP3, caspase-1, and IL-1β, in mice aorta was examined by RT-qPCR and FLICA and DAB staining. The protein expression of zonula occluden-1 (ZO-1), ZO-2, adiponectin (APN), and adiponectin receptor 1 (AdipoR1) in aortic endothelial cells was determined by immunofluorescence double staining. Intracellular reactive oxidative stress and nitric oxide (NO) production were monitored with fluorescence probes, dihydroethidium, and diaminofluorecein. Results HFD increased caspase-1 and IL-1β at mRNA and protein levels in endothelial cells of the aorta, and this was attenuated by voluntary running. HFD decreased ZO-1 and ZO-2 expression and reduced APN and AdipoR1 signaling; these were restored by running. The elevated intracellular superoxide (O2) production observed in HF-SED was ameliorated in HF-RUN. Finally, HF-RUN improved NO production in the aorta compared with HF-SED. Conclusions Our findings suggest that voluntary running ameliorates mechanisms associated with vascular dysfunction by suppressing NLRP3 inflammasome, improving NO production, and reducing oxidative stress. Such benefits of physical activity may be, at least in part, associated with APN-AdipoR1 signaling and tight junction protein expression.

The paleo diet is popular among the general population due to promoted weight loss and disease prevention benefits. We examined the effectiveness of a self-administered paleo diet in improving cardiometabolic disease risk factors. Overweight, physically inactive but otherwise healthy adults (males = 4, females = 3, age 32.7 ± 4.9 years, body mass index [BMI] 29.4 ± 2.4 kg/m2) habitually eating a traditional Western diet (1853.4 ± 441.2 kcal; 34.0% carbohydrate; 41.4% fat; 19.2% protein) completed an ad libitum self-administered paleo diet for 8 weeks. Height, weight, blood pressure, and a fasting blood sample were collected pre– and post–paleo dietary intervention. Blood samples were analyzed for fasting cardiometabolic disease biomarkers—including brain-derived neurotropic factor (BDNF), fibroblast growth factor (FGF) 21, and leptin. After 8 weeks, body mass (−5.3 kg, P = .008), BMI (−1.7 kg/m2, P = .002), serum leptin (−56.2%, P = .012), serum FGF21 (−26.7%, P = .002), and serum BDNF (−25.8%, P = .045) significantly decreased. Systolic and diastolic blood pressure were unchanged following the paleo dietary intervention ( P > .05). Average energy intake (−412.6 kcal, P = .016) significantly decreased with the paleo dietary intervention mostly due to a reduction in carbohydrate consumption (−69.2 g; P = .003). An 8-week self-administered paleo dietary intervention was effective in improving cardiometabolic disease risk factors in a healthy, physically inactive overweight adult population.

IntroductionOlder adults are at elevated risk for morbidity and mortality caused by influenza. Vaccination is the primary means of prophylaxis, but protection is often compromised in older adults. As resistance exercise mobilizes immune cells into muscle, it may enhance vaccination response.PurposeCompare antibody and cell mediated immune responses to influenza vaccination in older adults who performed eccentric resistance exercise immediately prior to vaccination to those who did not exercise.MethodsTwenty nine resistance training-naive older adults (20 women, 73.9 ± 5.3 years) were randomized to 1 of 3 groups: vaccination in the same arm that exercised (Ex-S), vaccination in the opposite arm that exercised (Ex-Op), and seated rest (No-Ex). Exercise consisted of 10 sets of 5 eccentric unilateral repetitions at 80% of the pre-determined concentric one repetition maximum. Lateral raises were alternated with bicep curls. No-Ex sat quietly for 25 min. Following exercise or rest, all received the 2018 quadrivalent influenza vaccine (Seqirus Afluria) in the non-dominant deltoid. Antibody titers against each influenza vaccine strain were determined by hemagglutinin inhibition assays at baseline, 6-, and 24-weeks post-vaccination. Influenza-specific T cells were quantified after stimulation with the vaccine by intracellular cytokine staining.ResultsNo significant group x time effects were found in antibody responses to any strain (interaction for A/H1N1: p = 0.682; A/H3N2: p = 0.644; B/Colorado/06/2017: p = 0.262; B/Phuket/3073/2013: p = 0.851). Groups did not differ in fold-increase of antibody titers 6- and 24-weeks post-vaccination. Influenza-specific T-cells did not differ between groups at any time (comparison at baseline: p = 0.985; 6-weeks: p = 0.889; 24 weeks: p = 0.857). One subject (Ex-S) reported flu-like symptoms 18 weeks post-vaccination.ConclusionAcute arm eccentric exercise did not influence antibody titers or cell mediated immune responses to the influenza vaccine delivered post-exercise in older adults. More strenuous exercise may be required for exercise to act as an adjuvant. ClinicalTrials.gov Identifier: NCT03736759.

Aging is associated with many chronic diseases that are maintained and perpetuated by immune dysregulation and chronic systemic inflammation. T-cells often undergo age-related changes, including an accumulation of memory cells, which places individuals at increased risk for novel infections and may predispose them to increased inflammation. Regular exercise training has been suggested to offset age-related changes in T-cells, but the majority of literature is derived from cardiorespiratory exercise (CRE) studies. Much less is understood about the T-cell response to resistance exercise (RE). The purpose of this study was to examine the effects of acute CRE and acute RE on the T-cell response among a cohort of physically active older adults (PA) compared to a cohort of physically inactive older adults (PI).METHODSTwenty-four healthy older adults (PA n=12; PI n=12; mean ± SD; age (yrs) PA 62 ± 5, PI 64 ± 5; height (cm) PA 170.9 ± 6.9, PI 162.9 ± 8.0; weight (kg) PA 69.3 ± 10.2, PI 68.2 ± 12.8; BMI (kg/m2) PA 23.9 ± 3.0, PI 25.6 ± 3.5) completed one bout of CRE and one bout of RE in a randomized order, both at a moderate intensity, and separated by at least 7 days. Blood samples drawn pre-exercise, post-exercise, and 1h post-exercise (recovery) were analyzed for CD4+ and CD8+ T-cells and their differentiation status using surface markers CD45RA, CD62L, and CD57, as well as for Th17 cells (CD4+ CD161+ CD196+) using flow cytometry.RESULTSPI had higher numbers of circulating CD57+ EMRA CD4+ T-cells (PA, mean ± SE, 1 ± 2 cells/uL; PI, 6 ± 2 cells/uL; p=0.01; z=2.32) than PA at pre-exercise. Both CRE and RE elicited a significant mobilization of highly-differentiated (CD45RA+ CD62L-; CD57+ CD45RA+ CD62L-) CD8+ T-cells into the circulation post-exercise in both PA and PI groups. Furthermore, CRE resulted in a decrease in the number of circulating Th17 cells post-exercise, while RE increased Th17 cell mobilization compared to the CRE response.CONCLUSIONTaken together, T-cells in PA and PI respond similarly to acute CRE and support previously reported data showing a significant mobilization of highly differentiated T-cells. The present study confirms that moderate intensity RE also elicits this response, but highlights potential differences between CRE and RE on the immune responses of T-cells, particularly in PI individuals.Clinical trial registrationThis research study was registered at clinicaltrials.gov NCT03794050

In the United States, overweight/obesity is more prevalent among those with low-income, higher income is related to greater leisure time physical activity (LTPA) and sedentary behavior (SB), which are inversely related to overweight/obesity. This study aimed to evaluate the role of LTPA and SB simultaneously in the income-overweight/obesity relationship. Cross-sectional data from the National Health and Nutrition Examination Survey (2007–2014) were utilized (n = 10,348 non-older adults (aged 20–59 years)). A multiple mediator structural equation model was conducted to evaluate the indirect effects from income to overweight/obesity (Body Mass Index ≥25 kg/m2) through LTPA and SB simultaneously, controlling for confounding variables, including diet, smoking, and alcohol consumption. As expected, greater income was negatively associated with overweight/obesity. Income indirectly influenced overweight/obesity through LTPA (Indirect effect: B = −0.005, CI = −0.01, −0.003), and through SB (Indirect effect: B = 0.008, CI = 0.005, 0.01), in opposing directions. The direct effect from income to overweight/obesity remained statistically significant. LTPA partially accounted for the negative relationship between income and overweight/obesity, SB reduced the strength of the negative relationship between income and overweight/obesity. Targeted behavior approaches for weight management may be beneficial. Increasing LTPA among adults with lower income and decreasing SB among adults with higher income may provide some overweight/obesity protection.

Older adults are at elevated risk for morbidity and mortality caused by influenza. Vaccination is the primary means of prophylaxis, but protection is often compromised in older adults. As acute eccentric resistance exercise mobilizes immune cells into muscle, it may enhance vaccination response. PURPOSE: Compare antibody responses to influenza vaccination in older adults who performed resistance exercise prior to vaccination to those who did not exercise. METHODS: 29 resistance training-naive older adults (20 women, 73.9 ± 5.3 years) were randomized to 1 of 3 groups: vaccination in the same arm that exercised (Ex-S), vaccination in the opposite arm that exercised (Ex-OP), and seated rest (No-Ex). Exercise was unilateral and consisted of 10 sets of 5 eccentric repetitions at 80% of the pre-determined concentric one repetition maximum. Lateral raises were alternated with bicep curls. No-Ex sat quietly for 25 min. Following exercise or rest, all subjects received the 2018 quadrivalent influenza vaccine (Seqirus Afluria) in the non-dominant deltoid. Antibody titers against the four influenza vaccine strains were determined by hemagglutinin inhibition assays at baseline, 6-, and 24-weeks post-vaccination. Group differences in antibody titers by time were assessed by restricted maximum likelihood mixed models. Fold-changes in antibody titers 6- and 24-weeks from baseline were compared between groups by Kruskal-Wallis tests. RESULTS: No significant group x time effects were found for any strain. Groups did not differ in fold-increase of antibody titers 6- and 24-weeks post-vaccination. Although seroconversion rates remained low, only one subject (Ex-S) reported flu-like symptoms 18 weeks post-vaccination. CONCLUSION: Acute arm eccentric exercise did not influence antibody titers to the influenza vaccine delivered post-exercise in older adults. More strenuous exercise may be required for exercise to act as an adjuvant. http://ClinicalTrials.gov Identifier: NCT03736759 U.S. NIH Grant/Contract: R03AG052778

Insufficient sleep during childhood can lead to physical and mental health issues. In adults, sleep disturbances have been associated with altered levels of stress hormones and inflammatory cytokines, but data in youth is lacking. The aim of this study was to explore relationships between objective measures of sleep and salivary biomarkers in children and adolescents. Participants (N = 55, aged 8–16 years, 53% female) wore an actigraph sleep monitor in their home for seven nights and completed sleep diaries and the School Sleep Habits Survey (SSHS). Participants also donated first waking saliva samples, which were later assayed for α-amylase (sAA), cortisol, interleukin (IL)-6, and IL-1β. While sAA was not associated with objective sleep it did show a positive association with self-reported sleep disturbance. Morning cortisol levels were associated with objective sleep variables, including minutes spent awake the night before sampling, and sleep efficiency and awakenings the night after sampling. Morning IL-6 was associated with prior night sleep efficiency and minutes spent awake the night after saliva sampling. Likewise, IL-1β levels were associated with sleep duration and sleep onset latency during the nighttime sleep period prior to and after saliva sampling. These results align with other data to indicate objective elements of sleep are related to salivary cortisol, IL-6, and IL-1β in youth. Thus, quality of sleep on the night prior to sampling should be considered when investigating levels of salivary mediators in children.

Acute exercise preferentially mobilizes cytotoxic T-cells, NK-cells and non-classical monocytes to the bloodstream under the influence of hemodynamic forces and/or β2-adrenergic receptor (β2-AR) signaling. However, the relative contribution of these mechanisms to the redeployment of the most exercise-responsive cell types is largely unknown. We determined the lymphocyte and monocyte subtypes mobilized to blood during exercise via β2-AR signaling whilst controlling for β1-AR mediated reductions in hemodynamic forces. In a randomized, double blind, complete cross-over design, 14 healthy cyclists exercised for 30-minutes at +10% of blood lactate threshold after ingesting: (1) a placebo, (2) a β1-preferential antagonist (10 mg bisoprolol), or (2) a non-preferential β1 + β2-antagonist (80 mg nadolol) across three trials separated by >7-days. Bisoprolol was administered to reduce hemodynamic forces (heart rate and blood pressure) during exercise to levels comparable with nadolol but without blocking β2-ARs. The mobilization of total NK-cells, terminally differentiated (CD57+) NK-cells, central memory, effector memory and CD45RA+ effector memory CD8+ T-cells; non-classical monocytes; and γδ T-cells were significantly blunted or abrogated under nadolol compared to both bisoprolol and placebo, indicating that the exercise-induced mobilization of these cell types to the blood is largely influenced by β2-AR signaling. Nadolol failed to inhibit the mobilization of classical monocytes, CD4+ T-cells (and their subsets) or naive CD8+ T-cells, indicating that these cell types are mobilized with exercise independently of the β2-AR. We conclude that the preferential mobilization of NK-cells, non-classical monocytes and differentiated subsets of CD8+ T-cells with exercise is largely dependent on catecholamine signaling through the β2-AR. These findings provide mechanistic insights by which distinct lymphocyte and monocyte subtypes are preferentially mobilized to protect the host from anticipated injury or infection in response to an acute stress response.

Purpose: To investigate the T-lymphocyte response to a period of increased training volume in trained females compared to habitual activity in female controls. Methods:Thirteen trained female (19.8±1.9yrs) soccer players were monitored during a two-week long high volume training period (increased by 39%) and thirteen female untrained (20.5±2.2yrs) controls were monitored during two-weeks of habitual activity. Blood lymphocytes, collected at rest, were isolated before and after the two-week period. Isolated lymphocytes were assessed for the cell surface expression of the co-receptor CD28, a marker of T-lymphocyte naivety, and CD57 a marker used to identify highly-differentiated T-lymphocytes. Co-expression of these markers was identified on helper CD4+and cytotoxic CD8+ T-lymphocytes. In addition a further population of γδ+T-lymphocytes were identified. Plasma was used to determine Cytomegalovirus (CMV) serostatus. Results: No difference was observed in the T-lymphocyte populations following the two-week period of increased volume training. At baseline the number of total CD3+, cytotoxic CD8+, naïve (CD8+CD28+CD57−), intermediate (CD8+CD28+CD57+) T-lymphocytes and the number and proportion of γδ+T-lymphocytes were greater in the trained compared to the untrained females (p

Infection with adenovirus 36 (Ad36) has been associated with risk of obesity in youth in some studies, but the seroprevalence of this virus has not been examined among all populations. As Hispanic-American youth are of greater risk for obesity than other American youth, we sought to determine the proportion of Ad36 seropositive (Ad36+) students in an urban middle school serving a Hispanic population. We further examined if Ad36+ students were more likely to have obesity, and if Ad36 serostatus impacted changes in weight status following a health intervention. We determined body mass index (BMI) at the beginning and end of a 16-week health intervention among 40 Hispanic-American middle-school students. Ad36 serostatus was determined by enzyme-linked immunsorbent assay (ELISA). Seventy percent of the students were Ad36+. Ad36+ and Ad36 seronegative (Ad36−) did not differ before or after the intervention in body weight measures. The odds of being classified as obese was 1.4 times greater among Ad36+ than Ad36− at baseline, and 2.4 times greater post-intervention, but these were not statistically significant. We report a high seroprevalence of Ad36 among a population of Hispanic-American students. Ad36 seropositivity was associated with a trend for a greater likelihood of having obesity, but did not impact response to a health intervention.

Acute exercise evokes an almost instantaneous lymphocytosis, followed by sustained lymphopenia that occurs within just 30–60 min after exercise cessation. The aim of this study was to characterize the immediate (order of minutes) post-exercise kinetics of lymphocyte and monocyte egress, and to determine whether this egress is associated with heart rate recovery following a single bout of steady state dynamic exercise. Eleven healthy subjects cycled for 30-min at ~70% of their estimated peak power. Blood samples were collected from an intravenous catheter before exercise, during exercise (E) at +15 and +30 min, and during passive recovery (R) at exactly +1, +2, +3, +4, +5 and +10 min after exercise cessation. Complete blood counts and flow cytometry were used to enumerate total monocytes, lymphocytes: CD3+ T-cells, CD4+ T-cells, CD8+ T-cells, NK-cells and γδ T-cells in whole blood. Both lymphocytes and monocytes displayed rapid egress kinetics, by R+3 the total numbers of all cell types examined were significantly lower than E+30. NK-cells egressed more rapidly than other lymphocyte subtypes, followed by CD8+, γδ, and then CD4+ T-cells. Further, the egress of NK-cells, CD4+, and CD8+ T-cells positively correlated with heart rate recovery after exercise cessation. In conclusion, lymphocyte and monocyte egress is rapid and occurs within minutes of exercise recovery, underscoring both the importance of collection time for post exercise blood samples, and the use of intravenous catheters to capture peak cell mobilization. The rate of egress may be dependent on how quickly hemodynamic equilibrium is restored on cessation of exercise and is, therefore, likely to be influenced by individual fitness levels.

The beginning of a lifestyle intervention is a sensitive time, as doing “too much too quickly” may stress the immune system, resulting in an increase in upper respiratory symptoms and, consequently, attrition. However, “too little too slowly” may not align with patients’ motivation to change and may also result in attrition. There is also evidence that early weight loss is predictive of long-term maintenance of goal weight. Health care providers are frequently presented with contradictory information on the best model to promote enduring lifestyle change. Best practice dictates that health care provider acknowledge their patients’ motivation to change and incorporate each individual’s goals in designing the lifestyle change intervention. Additional support and advice may be warranted at the beginning of an intervention to promote the patient’s health and avoid attrition.

Natural Killer cells are cytotoxic lymphocytes that recognize and eliminate tumor cells. Exercise enhances NK cell cytotoxic activity (NKCA), yet the underlying mechanisms are not fully understood. Exercise-induced shifts in NK-cell subsets has been proposed as one mechanism. Alternatively, exercise alters stress hormone and cytokine levels, which are also known to affect NKCA. AIM: Determine the role(s) of exercise-induced shifts in the proportions of NK-cell subsets found in the blood, and changes in serum IL-2, IL-6, IL-12, IFN-γ, TNF-α and cortisol, on exercise-induced changes in NKCA. METHODS: Twelve adults cycled 30 min at 115% of their lactate threshold power. Peripheral blood mononuclear cells (PBMCs) and serum were isolated from blood collected pre-, post-, and 1 h post-exercise. To investigate the effect of shifts in NK-cell subsets, pre-, post- and 1 h post-exercise NK cells were incubated with target cells (K562 and U266) in the presence of autologous pre-exercise serum. The effects of hormones and cytokines released during exercise were determined by incubating pre-exercise PBMCs with tumor target cells (K562 and U266) in the presence of pre-, post-, and 1 h post-exercise serum. NKCA and phenotypes were assessed by flow cytometry. RESULTS: Although exercise mobilized high-differentiated NK cell subsets (NKG2A-/KIR+), NKCA per cell was not altered post-exercise in the presence of pre-exercise serum. Conversely, 1 h post-exercise serum significantly increased the cytotoxicity of pre-exercise NK cells against HLA-expressing target cells (U266). This increase associated with lower levels of cortisol, and occurred when serum contained higher levels of IFN-γ. CONCLUSIONS: Exercise-induced shifts in NK-cell subsets did not fully explain changes in NKCA. Rather, factors present in serum during exercise recovery enhanced NKCA against target cells. Our results suggest lower cortisol and higher IFN-γ levels may explain exercise-induced changes in NKCA.

Latent cytomegalovirus (CMV) infection has been shown to alter the lymphocyte response to acute aerobic exercise, likely due to the corresponding increase in exercise-responsive memory CD8(+) T cells. It is unknown if latent infection with another herpesvirus, herpes simplex virus 1 (HSV-1), also plays a role in shaping the lymphocyte response to exercise.Thirty-two men (ages 39.3 ± 14.7 yr) counterbalanced by CMV and HSV-1 serostatus (positive/negative) cycled for 30 min at ∼80% peak power. Blood sampled before, immediately after, and 1 h after exercise was analyzed by flow cytometry for T-cell subset enumeration.In resting blood, HSV-1(+) had fewer lymphocytes, CD4(+) T cells, KLRG1(-) CD28(+) CD4(+) T cells, and CD45RA(-)CCR7(+)CD4(+) T cells than HSV-1(-), whereas CMV(+) had increased numbers of lymphocytes, CD8(+) T cells, KLRG1(+)CD28(-)CD4(+) and CD8(+) T cells, and CD45RA(+)CCR7(-)CD8(+) T cells and a lower CD4:CD8 T-cell ratio than CMV(-). After exercise, CMV(+) had a greater mobilization of CD8(+) T cells, KLRG1+CD28(-)CD4+ and CD8(+) T cells, and CD45RA+CCR7(-)CD8+ T cells independently of HSV-1 serostatus, as well as a greater egress of these subsets 1 h after exercise. HSV serostatus did not influence total CD8(+) T-cell response to exercise.The impact of latent CMV infection on the redeployment of T-cell subsets with exercise is independent of HSV-1 infection. This is most likely due to the unique ability of CMV to alter the composition of the memory T-cell pool in favor of exercise-responsive T-cell subsets.

Cancer incidence increases with advancing age. Over 60% of new cancers and 70% of cancer deaths occur in individuals aged 65 years or older. One factor that may contribute to this is immunosenescence - a canopy term that is used to describe age-related declines in the normal functioning of the immune system. There are multiple age-related deficits in both the innate and adaptive systems that may play a role in the increased incidence of cancer. These include decreased NK-cell function, impaired antigen uptake and presentation by monocytes and dendritic cells, an increase in 'inflammaging', a decline in the number of naïve T-cells able to respond to evolving tumor cells, and an increase in functionally exhausted senescent cells. There is consensus that habitual physical exercise can offer protection against certain types of cancer; however the evidence linking immunological mechanisms, exercise, and reduced cancer risk remain tentative. Multiple studies published over the last two decades suggest that exercise can mitigate the deleterious effects of age on immune function, thus increasing anti-cancer immunity. The potential ameliorative effect of exercise on these mechanisms include evidence that physical activity is able to stimulate greater NK-cell activity, enhance antigen-presentation, reduce inflammation, and prevent senescent cell accumulation in the elderly. Here we discuss the role played by the immune system in preventing and controlling cancer and how aging may retard these anti-cancer mechanisms. We also propose a pathway by which exercise-induced alterations in immunosenescence may decrease the incidence of cancer and help improve prognosis in cancer patients.

This study compared the acute immune response, inflammation, and lipid peroxidation to a 75 km cycling time trial in male athletes testing positive or negative for latent cytomegalovirus (CMV) infection.Trained cyclists (N = 20) were tested for CMV serostatus, and cycled 75 km on a mountainous course using indoor trainers with continuous workload monitoring. Pre-, post-, and 1 h post-exercise blood samples were analyzed for total blood leukocyte counts, blood granulocyte (GR) and monocyte (MO) phagocytosis (PHAG) and oxidative burst activity (OBA), four plasma cytokines, and plasma F2-isoprostanes.Forty percent of the subjects tested positive for CMV. No differences in subject characteristics were found between CMVpos and CMVneg groups. Mean power (57.3 ± 1.6, 59.4 ± 1.8 % maximal Watts, p = 0.803), heart rate (87.0 ± 1.0, 86.5 ± 1.3 % maximal heart rate, p = 0.376), and total time (2.56 ± 0.08, 2.60 ± 0.08 h, p = 0.744) to complete the 75 km cycling time trial did not differ between CMVpos and CMVneg groups. Whereas exercise induced significant changes in total blood leukocyte counts, GR and MO-PHAG, four plasma cytokines, and plasma F2-isoprostanes (p 0.05, ω(2) 0.03), these exercise-induced changes did not differ between CMVpos and CMVneg groups (p 0.05, ω(2) 0.01).CMV serostatus does not appear to influence these innate immune responses or markers of inflammation and lipid peroxidation in response to a single bout of heavy exertion.

γδ T-cells are cytotoxic effector cells that preferentially migrate to peripheral tissues and recognize many types of antigen. We examined the effects of age and viral serology on the exercise responsiveness of γδ T-cells. Blood was collected from 17 younger (age: 23–35 yrs) and 17 older (50–64 yrs) healthy males matched for cytomegalovirus (CMV), Epstein-Barr virus, herpes simplex virus-1 and Parvovirus B19 serologic status before and after a single bout of cycling exercise. Older had lower numbers and proportions of γδ T-cells than younger, while CMV was associated with increased numbers and proportions of γδ T-cells in younger but not older. Exercise evoked a ∼2-fold increase in circulating γδ T-cell numbers. The magnitude of this response was 3-times greater in younger compared to older, and 1.6-times greater in younger CMV-infected compared to younger non CMV-infected. To conclude, γδ T-cell numbers and exercise responsiveness decreases with age and may contribute to impaired immunosurveillance after acute acute physical stress.

Exercise alters the percentage of CD8 + T-cells in the bloodstream expressing type I and type II cytokines. It is unknown if this reflects a change in cytokine expression within individual cells, or whether these observations result from the exercise-induced shift in the proportions of early/intermediate (CD27 + ) and late (CD27 − ) differentiated cells, which have vastly different cytokine profiles. 16 males cycled for 60 min at 95% maximal steady state. Mononuclear cells isolated from blood collected before, immediately after, and 1 h after exercise were cultured overnight with and without phytohaemagglutinin stimulation. CD8 + T-cells were assessed for differentiation markers and intracellular cytokine expression by flow cytometry. The numbers and percentage of CD27 − CD8 + T-cells increased immediately after exercise and fell below pre-exercise values 1 h later. At 1 h after exercise, an increased number and percentage of CD8 + T-cells expressing IL-2, IFN-γ, TNF-α, IL-6, IL-4, and IL-10 was observed in both stimulated and unstimulated cells. The cytokine response to exercise was confined to CD27 − CD8 + T-cells, although cytokine expression among CD8 + T-cells was highest when the proportion of CD27 − CD8 + T-cells was lowest. Moreover, the cytokine response to exercise could be predicted by the number of late cells in resting blood: cytokine expression was highest among those with low resting proportions of late cells. We conclude that exercise-induced changes in the percentage of CD8 + T-cells expressing cytokines are not due to proportional shifts in early/intermediate and late differentiated T-cells. Exercise may prime late-differentiated blood CD8 + T-cells to initiate effector functions in preparation for their extravasation into the tissues.

The magnitude of lymphocytosis following exercise is directly related to exercise intensity. Infection with cytomegalovirus (CMV) also augments lymphocytosis after exercise. It is not known if the enhanced T‐cell response to exercise due to CMV depends on exercise intensity. Furthermore, exercise‐induced changes in T‐cell expression of type I and type II cytokines are thought to be intensity dependent, but direct comparisons are lacking. The aim of this experiment was to determine if CMV affects the exercise‐induced redistribution of T‐cell subsets at varying intensities, and determine the effect of exercise intensity on CD8+ T‐cell cytokine expression. Seventeen cyclists (nine CMV seropositive; CMV+) completed three 30 min cycling trials at −5, +5, and +15% of blood lactate threshold (LT). T‐cell subsets in blood and intracellular expression of type I (IL‐2, interferon(IFN)‐γ) and type II (IL‐4, IL‐10) cytokines by CD8+ T cells pre, post, and 1‐h post‐exercise were assessed by flow cytometry. Independently of CMV, T‐cell subset redistribution was greater after +15%LT compared to −5%LT (P

Cold temperature and exercise independently impose stress on the human body that can lead to circulatory and metabolic changes, and depress the immune system. Multiple stressors applied together may amplify this immunodepression, causing greater immune impairment and heightened infection risk than with either stressor alone. As such, winter athletes and other persons who work or physically exert themselves in cold temperatures may have greater levels of stress-induced immune impairment than would be expected under mild temperatures. This review examines the literature regarding changes to physiological and immunological parameters arising from exposure to cold temperatures and to exercise. Even brief exposure to cold leads to increased levels of norepinephrine and cortisol, lymphocytosis, decreased lymphoproliferative responses, decreased levels of TH1 cytokines and salivary IgA, and increased lactate levels during exercise. Whether these changes lead to increased susceptibility to infection, as suggested by some epidemiological reports, remains to be determined. Although there is some evidence that exercising in temperatures near 5°C leads to greater immune impairment compared to exercising in milder temperatures, there is a need to explore the effects of exercise on immunity in the subfreezing conditions typically encountered by winter athletes. This is required to fully determine the extent to which performing vigorous exercise in subfreezing temperatures amplifies exercise-induced immune impairment and infection risk.

Activation of the nucleotide‐binding oligomerization domain‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome mediates the release of pro‐inflammatory cytokine interleukin (IL)‐1β and thereby plays a pivotal role in the inflammatory response in vascular pathology. An active lifestyle has beneficial effects on inflammation‐associated vascular dysfunction in obesity. However, it remains unclear how physical activity regulates NLRP3 inflammasome‐mediated vascular dysfunction in obesity. Therefore, we explored the protective effect of physical activity on NLRP3 inflammasome‐associated vascular dysfunction in mouse hearts, and the potential underlying mechanisms. C57BL/6J male mice were randomly divided into four groups: (1) control low‐fat diet (LF‐SED), (2) LF diet with free access to a voluntary running wheel (LF‐RUN), (3) high‐fat diet (HF‐SED; 45% of calories from fat), and (4) HF‐RUN. We examined NLRP3 inflammasome‐related signaling pathways, nitric oxide (NO) signaling, and oxidative stress in coronary arterioles to test effects of HFD and physical activity. Voluntary running reduced NLRP3 inflammasome and its downstream effects, caspase‐1 and IL‐1β in coronary arteriole endothelium of obese mice in immunofluorescence staining. HF‐RUN attenuated HFD‐dependent endothelial NO synthase (eNOS) reduction and thus increased NO production compared to HF‐SED. HFD elevated intracellular superoxide production in coronary arterioles while voluntary running ameliorated oxidative stress. Our findings provide the first evidence that voluntary running attenuates endothelial NLRP3 inflammasome activation in coronary arterioles of HFD feeding mice. Results further suggest that voluntary running improves obesity‐induced vascular dysfunction by preserved NO bioavailability via restored expression of eNOS and reduced oxidative stress.

The ex vivo generation of monocyte-derived-dendritic cells (mo-DCs) has facilitated the use of DCs in immunotherapy research. However, low blood monocyte numbers frequently limit the manufacture of sufficient numbers of mo-DCs for subsequent experimental and clinical procedures. Because exercise mobilizes monocytes to the blood, we tested if acute dynamic exercise by healthy adults would augment the generation of mo-DCs without compromising their differentiation or function. We compared mo-DC generation from before- and after-exercise blood over 8-days of culture. Function was assessed by FITC-dextran uptake and the stimulation of autologous cytomegalovirus (pp65)-specific-T-cells. Supporting the hypothesis, we found a near fourfold increase in number of mo-DCs generated after-exercise. Furthermore, relative FITC-dextran uptake, differentiation rate, and stimulation of pp65-specific-T-cells did not differ between before- and after-exercise mo-DCs. We conclude that exercise enhances the ex vivo generation of mo-DCs without compromising their function, and so may overcome some limitations associated with manufacturing these cells for immunotherapy.

The adoptive transfer of viral-specific T-cells (VSTs) is highly effective in treating viral infections after allogeneic hematopoietic stem cell transplant. Unfortunately, adoptive T-cell therapy is not available for a large number of patients due to logistical constraints associated with isolating and manufacturing enough VSTs from healthy donors. We have shown that a single exercise bout reliably augments the ex vivoexpansion of VSTs and thus might be useful as a clinical adjuvant to boost the manufacture of VSTs from healthy donors. We sought to determine if the augmenting effects of exercise on VST expansion are dependent on β2 adrenergic receptor (β2AR) signaling. Using a randomized cross-over and double-blinded design, ten subjects performed 30-min of steady state cycling exercise 3 h after ingesting (i) a placebo, (ii) a β1 + 2AR antagonist (nadolol), or (iii) a β1AR antagonist (bisoprolol). PBMCs isolated before and after exercise were stimulated with Adenovirus (AdV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) peptide antigens and cultured for 8 days, after which VSTs were enumerated by IFNγ ELISPOT. Compared to resting conditions, exercise augmented the expansion of VSTs in the placebo and bisoprolol trials (38.2% and 57.9% increases), but not in the nadolol trial (3.3% decrease). We conclude that the augmenting effects of exercise on VST expansion are dependent on β2AR signaling, highlighting the β2AR as a potential target to increase the potency of T-cell therapeutics.

Acute exercise evokes an almost instantaneous lymphocytosis, which is followed by sustained lymphopenia within just 30–60 min of exercise cessation. The aim of this study was to characterize for the first time the immediate (order of minutes) post-exercise kinetics of lymphocyte egress, and to determine if lymphocyte egress is associated with heart rate recovery following exercise. 11 healthy subjects exercised for 30-min at 80 percent peak cycling power. Blood samples were collected from an intravenous catheter before exercise, during (+15 and + 30 min) exercise, and at exactly +1, +2, +3, +4, +5 and +10 min after exercise cessation. Complete blood counts and flow cytometry was used to enumerate total lymphocytes, CD3 + T-cells, CD4 + T-cells, CD8 + T-cells, NK-cells and gamma-delta T- cells in whole blood. Compared to the peak lymphocyte count during exercise, the lymphocyte count had fallen significantly (−14 percent) after just 2 min of exercise recovery. After 5 and 10 min of exercise recovery, the lymphocyte count was −23 percent and −28 percent of peak values, respectively. NK cells were fastest to egress peripheral blood, followed by CD8 + T-cells. Further, the egress of both NK-cells and CD8 + T-cells was strongly correlated with recovery heart rate upon exercise cessation. In conclusion, lymphocyte egress occurs within the first few minutes of exercise recovery and may be dependent on how quickly hemodynamic equilibrium is restored.

Studies aimed at determining the contribution of beta-adrenergic receptor signaling to stress-induced lymphocyte mobilization have failed to control for hemodynamic perturbations that accompany psychological stress, exercise, and/or epinephrine infusion. We aimed to determine the relative contribution of beta2-adrenergic receptor (B2-AR) signaling to the mobilization of various lymphocyte and monocyte subtypes with exercise while controlling for hemodynamic shear stress. Fourteen healthy subjects underwent 30 min of steady state cycling exercise under 3 different conditions separated by at least 7-days: placebo; beta1-preferential antagonist (10 mg bisprolol); and non-preferential beta1 and beta2- antagonist (80 mg nadolol). Drugs were administered 3 h prior to exercise in a randomized double-blind cross-over design. Blood samples were collected prior to drug administration, immediately before exercise, and immediately after exercise for immunophenotyping by flow cytometry. Compared to placebo, bisoprolol and nadolol reduced exercising heart rate and blood pressure to comparable levels, indicating that hemodynamic perturbations were similar between the two drug trials. Several lymphocyte and monocyte subpopulations (CD8 T-cells: CD28negCD27neg, CD45RAposCD62Lneg, KLRG1posCD57pos, KLRG1posCD57neg, CD45RAnegCD62Lneg, CD45RAnegCD62Lpos; NK Cells: NK cells (all), NKG2CposCD57neg, NKG2CnegCD57pos, NKG2CnegCD57neg; non-classical monocytes (CD14posCD16pos); and gamma delta T-cells) exhibited a B2-AR dependent response, as indicated by a blunted mobilization with nadolol compared to both bisoprolol and placebo. We conclude that 28–61 percent of the ‘exercise responsive’ lymphocytes and monocytes are dependent on B2-AR signaling for their mobilization into the peripheral blood compartment.

Natural Killer-cell cytotoxicity (NKCA) increases during recovery from exercise. The mechanism(s) underlying enhanced NKCA remain unknown. We therefore investigated the role of exercise-induced changes in cortisol and NK-cell subsets on NKCA. Methods Thirteen adults (7 women; 32 ± 7 years) cycled 30 min 15% above lactate threshold. NK-cells from pre-, post-, and 1 h post-exercise were incubated with U266 tumor-target cells in the presence of autologous serum. NKCA was assessed after 4 h in a flow cytometry based assay. To determine the effect of cortisol released during exercise, pre-exercise NK-cells and targets were incubated with pre-, post- and 1 h post-exercise serum. To determine the effect of shifts in NK-cell subsets, pre-, post-, and 1 h post-exercise NK-cells and targets were incubated with pre- exercise serum. Serum cortisol was assessed by ELISA. Results were analyzed using linear mixed models. Results The NKCA of pre-exercise NK-cells was enhanced in the presence of 1 h post-exercise serum (p Conclusions Serum obtained 1 h post-exercise enhanced resting NKCA and decreased the proportion of inhibitory NK-cells. This suggests that factors present in serum after exercise can alter effector cell function. Future work will analyze cytokines present in 1 h post-exercise serum.

Regular physical exercise is associated with increased longevity and a lower risk of developing several age-associated diseases. In addition, regular exercise has been purported as a simple lifestyle intervention to counteract the deleterious effects of age-associated changes in immunity known as immunosenescence. Etiology of immunosenescence is multifaceted and can impact on both arms of the immune system. Since 1990, several longitudinal ageing studies using aerobic- and/or resistance-based exercise provided growing information on the benefits of exercise in both innate immunity and adaptive immunity. Regular exercise can improve responses to vaccines, NK-cell function, neutrophil phagocytic activity, and T-cell proliferation. It also reduces circulatory inflammatory mediators and inflammatory response to bacterial challenge. These findings provide a strong indication that habitual exercise has immune regulatory properties and may help delay the onset of immunosenescence.

Dynamic exercise evokes a rapid redeployment of cytotoxic T cell subsets with high expression of β2 adrenergic receptors, presumably to enhance immunosurveillance during acute stress. As this response is affected by age and infection history, this study examined latent CMV infection as a potential confounder to age-related differences in blood CD8+ T-cell responses to exercise. Healthy young (n=16) and older (n=16) humans counterbalanced by CMV IgG serostatus (positive or negative) exercised for 30-min at ∼80% peak cycling power. Those with CMV redeployed ∼2-times more CD8+ T-cells and ∼6-times more KLRG1+/CD28- and CD45RA+/CCR7- CD8+ subsets than non-infected exercisers. Seronegative older exercisers had an impaired redeployment of total CD8+ T-cells, CD45RA+/CCR7+ and KLRG1-/CD28+ CD8+ subsets compared to young. Redeployed CD8+ T-cell numbers were similar between infected young and old. CMVpp65 specific CD8+ cells in HLA/A2(∗) subjects increased ∼2.7-fold after exercise, a response that was driven by the KLRG1+/CD28-/CD8+ subset. Stimulating PBMCs before and after exercise with CMVpp65 and CMV IE-1 antigens and overlapping peptide pools revealed a 2.1 and 4.4-fold increases in CMVpp65 and CMV IE-1 IFN-γ secreting cells respectively. The breadth of the T cell response was maintained after exercise with the magnitude of the response being amplified across the entire epitope repertoire. To conclude, latent CMV infection overrides age-related impairments in CD8+ T-cell redeployment with exercise. We also show for the first time that many T-cells redeployed with exercise are specific to CMVpp65 and CMV IE-1 antigens, have broad epitope specificity, and are mostly of a high-differentiated effector memory phenotype.

The ex vivo expansion of tumor-associated-antigen (TAA)-specific-T-cells from healthy donors for adoptive transfer to cancer patients helps prevent relapse following hematopoietic stem cell transplantation. However, the procedure is limited by the difficulties in expanding sufficient numbers of TAA-specific-T-cells from healthy donors. Moreover, low blood monocyte numbers limit the manufacture of monocyte-derived-dendritic cells (Mo-DC) that are used to prime TAA-specific-T-cells. Because acute dynamic exercise mobilizes monocytes and T-cells to peripheral blood, we hypothesized that a single bout of exercise would augment the ex vivo expansion of Mo-DC and TAA-specific-T-cells without compromising their function. 25 healthy adults completed a bout of maximal exercise. Mo-DC generated before (PRE) and after (POST) exercise were pulsed with melanoma (MAGE-A4, PRAME) and leukemia (WT-1) associated antigen to expand autologous TAA-specific-T-cells, also obtained PRE and POST exercise. POST yielded a threefold increase in mo-DC number without compromising function; FITC dextran uptake, differentiation rate and the priming of autologous CMVpp65-specific T-cells did not differ between PRE and POST mo-DC. T-cells expanded POST had more MAGE-A4- and PRAME-specific-cells in 70% and 61% of all participants respectively. In those ‘exercise-responders’, MAGE-A4 and PRAME-specific T-cells increased 4-fold and 6-fold with exercise respectively. We conclude that exercise enhances the expansion of TAA-specific-T-cells and mo-DC ex vivo without compromising their function and may help overcome some of the limitations associated with expanding these cells for adoptive transfer immunotherapy.

Acute-exercise facilitates the trafficking of peripheral blood CD8+ T-cells, preferentially mobilizing effector-memory and senescent cells. Although this response appears to be greater in older subjects, it is also amplified in young people with latent cytomegalovirus (CMV) infection. As CMV prevalence increases with age, these age-related differences in the CD8+ T-cell response to exercise may be due to CMV. Sixteen young (Y, 20–35 years) and 16 older (O, 50–64 years) subjects cycled for 30-min at 80% peak-power. Eight participants in both Y and O were seropositive (pos) for CMV. Blood lymphocytes isolated before, immediately after and 1 h after exercise were analyzed for numbers and proportions of CD3+/CD8+ T-cells and, naive (KLRG1−/CD28+), memory (KLRG1+/CD28+) and senescent (KLRG1+/CD28−) subsets. Exercise increased numbers of senescent, memory and naive CD8+ T-cells, followed by an egress 1 h later. Age (+32%), CMV (+24%), and age-×-CMV interaction effects were found for proportions of senescent CD8+ T-cells. For senescent cells, CMVpos had an amplified ingress (61 vs 29%) and egress (66 vs 30%) compared to CMVneg, while Yneg and Oneg did not differ for ingress (29 vs 29%) or egress (31 vs 29%). However, this response was greater in Opos than Ypos for ingress (66 vs 55%) and egress (82 vs 50%). In conclusion, these data indicate that latent CMV infection may account for the apparent age-related effects on the CD8+ T-cell response to acute exercise.

Human space exploration provides great technological, medical and academic advances to humanity, but also poses many threats to the health of the crew. Astronauts are subjected to a myriad of both physical and psychological stressors that may negatively affect the immune system and increase the risk of an adverse health event in flight. In this ongoing study, we compared immune cell phenotypes and NK-cell activity (NKCA) between astronauts and controls 5-months before a 6-month mission to the International Space Station (ISS). Blood samples were taken from 6 astronauts and 6 non-astronaut controls and assayed for immune cell phenotypes and NKCA by flow cytometry. Astronauts had lower proportions and numbers of naive KLRG1−/CD28+ (p 0.05). We conclude that astronauts display only small baseline differences in T-cell phenotype and NKCA compared to controls when assessed 5-months prior to launch. This study will continue to monitor immune function changes in these astronauts and ground-based controls during and after a 6-month mission to the ISS.

Cytomegalovirus (CMV) infection markedly expands NKG2C+/NKG2A- NK-cells, which are potent killers of infected cells expressing the non-classical MHC molecule HLA-E. As HLA-E is overexpressed in several bloodborne malignancies, we examined the impact of latent CMV infection and acute exercise on NK-cell cytotoxic activity (NKCA) against a wide range of tumor target cells with varying levels of HLA-E expression. In resting blood, the expansion of NKG2C+ NK-cells with CMV was associated with strong anti-leukemia (K562) and anti-myeloma (U266) NKCA that was proportionate to the level of target cell HLA-E expression. NKCA against transfected (HLA-E-bright) 221.AEH cells was 3-times higher in those with CMV, but no effect of CMV was found on NKCA against HLA-E-negative 721.221 cells. Blocking the interaction between NKG2C and HLA-E completely eliminated the effect of CMV on NKCA against 221.AEH cells. Although NK-cells were redeployed in large numbers with exercise, NKG2C+ NK-cells were among the poorest responders of the NK-cell subsets to 30-min of cycling exercise. This contributed to a blunted exercise-induced redeployment of total NK-cells in those with CMV. Moreover, NKCA against U266 and 221.AEH target cells was enhanced during exercise recovery, but not in those with CMV. In conclusion, latent CMV infection enhances NKCA through preferential expansion of NKG2C+ NK-cells; however, these cells respond poorly to a single bout of exercise indicating that CMV may impair acute stress-induced immunosurveillance.

The immune risk profile (IRP) is an array of immunological biomarkers that is associated with decreased vaccine efficacy, increased disease susceptibility and 3–5 year mortality in the elderly. Increased proportions of KLRG1 + CD28-CD8 (senescent) T-cells and latent cytomegalovirus (CMV) infection are key components of the IRP. We have previously shown that high aerobic fitness levels (determined by VO2 max) are associated with a decreased accumulation of senescent T-cells during aging, but it is not known if fitness affects CMV prevalence or viral load. T-cell phenotypes and CMV status was determined in 74 healthy men (aged 18–64) categorized as “High Fit” (n = 36) or “Low Fit” (n = 38) according to age-adjusted VO2max scores. High aerobic fitness was associated with lower proportions of senescent CD8+ T-cells (23.0% v 46.6%; p